The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Dasatinib is an oral protein tyrosine kinase inhibitor used to cure adult chronic myelogenous leukemia (CML), and acute lymphatic leukemia (ALL) with positive Philadelphia chromosome. It is available under the trade name of SPRYCEL® as kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ All) with resistance or intolerance to prior therapy in the recommended dose of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg and 140 mg tablets.
Dasatinib is chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide of Formula (I) and its monohydrate of Formula (IA) chemical structure is as below.

U.S. Pat. No. 6,596,746 B1 (the U.S. '746 Patent) discloses the process for the preparation of dasatinib (I) by reacting compound of Formula 3 with N-(2-hydroxyethyl)piperizine at 80° C. as shown in Scheme-1 as below.

U.S. Pat. No. 7,491,725 B2 (the U.S. '725 B2 Patent) discloses dasatinib monohydrate and dasatinib butanol solvate and process for their preparation. Scheme-2 shows a general process for the preparation of Dasatinib as disclosed in the U.S. '725 B2. Intermediate 3 and N-(2-hydroxyethyl)piperazine are heated together in a solvent system comprising n-butanol as a solvent and diisopropyl-ethylamine (DIPEA) as a base. On cooling of the reaction mixture, Dasatinib precipitates out which is isolated by filtration.

U.S. Pat. No. 8,242,270 B2 (the U.S. '270 Patent) discloses two ethanol solvates of dasatinib i.e. E2-1 and TIE2-1. The U.S. '270 patent also discloses two anhydrous forms of dasatinib i.e. N-6 and T1H1-7 and processes for their preparation.
U.S. Pat. No. 7,973,045 B2 (the U.S. '045 Patent) discloses various solvates and hydrates of dasatinib. In particular, the U.S. '045 patent discloses anhydrous Form-B, isopropanol solvate and acetone solvate for dasatinib.
The U.S. '045 patent also discloses the processes for the preparation of amorphous dasatinib. In particular, the example 26, 50, 56 and 60 discloses the process for the preparation of amorphous dasatinib. The example-26 discloses reacting compound 1, N-(2-hydroxyethyl)piperizine in presence of N-ethyldiisopropylamine in dimethylformamide at 90° C. The amorphous form was obtained by cooling the solution and dilution with water at 0° C. The example-26 when performed using the conditions provided therein resulted in amorphous dasatinib having residual DMF. The TGA of amorphous dasatinib discloses 48% loss of residual mass indicating higher residual solvents, which makes it unsuitable for pharmaceutical use.
The example 50, 56 and 60 discloses the processes for the preparation of amorphous dasatinib wherein dasatinib crystalline Form A21 was used as starting compound. Further, the solvents like 1,2-dichlorobenzene, benzyl alcohol and propyl glycol, respectively were used in examples 50, 56 and 60 wherein wet samples were analyzed for XRD to obtain amorphous form. However, the X-ray powder diffraction pattern as depicted in FIG. 35, FIG. 43 and FIG. 99 represented as amorphous dasatinib is a mixture of crystalline and amorphous form.
The example 50a further discloses that dasatinib amorphous obtained by example 50 (wet-cake) was dried in a bottle in a conventional oven overnight at 55° C. The obtained sample was analyzed by XRD and found to be Form BA, which is crystalline form. Therefore, the presence of residual solvents during drying will convert the amorphous form to crystalline form.
Therefore, the prior art process provides amorphous dasatinib containing higher amount of residual solvent which is not suitable for pharmaceutical developments. When the amorphous dasatinib having higher residual solvents is subjected to stability conditions, it is observed that it converts to crystalline form.
Therefore, the processes disclosed in the U.S. '045 patent may not be suitable for large scale preparation of amorphous dasatinib. The amorphous forms disclosed are not dry and may not be free from residual solvents. The samples were analyzed as wet-cake which is a mixture of crystalline and amorphous form.
U.S.PG-Pub. No. 2012/0309968 A1 discloses polymorph I of dasatinib monohydrate and polymorph II of dasatinib, their preparation methods and pharmaceutical compositions containing the same.
International (PCT) Publication WO 2013/065063 A1 discloses process for the preparation of anhydrous and monohydrate form of dasatinib which is incorporated herein as reference in its entirety.
Dasatinib is practically insoluble in water or organic solvents like methanol, ethanol, propanol, isopropanol, butanol and the like even in the condition of heating. Therefore, higher amount of solvents are required which is disadvantageous in industrial production. The method reported in the U.S. '725 B2 discloses use of ethanol and water mixture resulting in the formation of monohydrate.
The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e. g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e. g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form to that of an amorphous form may be important in pharmaceutical processing. For example, an amorphous form may provide better bioavailability than the crystalline form. Thus, a present amorphous form can provide a useful alternative for dasatinib monohydrate and may be useful for formulations which can have better stability, solubility, storage, compressibility etc important for formulation and product manufacturing and doesn't degrade to crystalline forms of dasatinib.
Therefore, it is desirable to have stable amorphous form of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.
In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of amorphous form of dasatinib. The amorphous form provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is free flowing powder.